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Effects of KP-496, a novel dual antagonist for leukotriene D4 and thromboxane A2 receptors, on contractions induced by various agonists in the guinea pig trachea.
Allergol Int. 2006 Dec; 55(4):403-10.AI

Abstract

BACKGROUND

A dry powder inhaler of KP-496 is currently in clinical development in Japan as an anti-asthmatic agent. The aim of this study was to evaluate the in vitro pharmacological profile of KP-496.

METHODS

The antagonistic activities of KP-496 for leukotriene (LT) D(4) and thromboxane (TX) A(2) receptors were examined using the LTD(4)- and U46619-induced contractions of the isolated guinea pig trachea. The selectivity of KP-496 was examined using various agonist-induced contractions in the isolated guinea pig trachea.

RESULTS

KP-496 produced parallel rightward shifts of the LTD(4) and U46619 concentration-response curves in a concentration-dependent manner. Schild plot analyses of the antagonistic activities of KP-496 demonstrated that it is a competitive antagonist for LTD(4) and TXA(2) receptors with pA(2) values of 8.64 and 8.23, respectively. The LTD(4) antagonistic activity of KP-496 was comparable to that of pranlukast and zafirlukast but was more potent than that of montelukast. The TXA(2) antagonistic activity of KP-496 was comparable to that of seratrodast. KP-496 and seratrodast also inhibited the prostaglandin (PG) D(2)- and PGF(2alpha)-induced contractions of the isolated guinea pig trachea. KP-496 had no effect on the histamine-, acetylcholine-, serotonin- and substance P-induced contractions of the isolated guinea pig trachea.

CONCLUSIONS

These results indicate that KP-496 is a selective dual antagonist for LTD(4) and TXA(2) receptors. LTD(4) and TXA(2) play important roles in asthma, and antagonists for these mediators are being used for the treatment of asthma. Thus, KP-496 is expected to become a novel potent therapeutic agent for asthma.

Authors+Show Affiliations

Pharmacology Department, Central Research Laboratories, Kaken Pharmaceutical Co., Ltd., Kyoto, Japan. ishimura_masakazu@kaken.co.jpNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

17130683

Citation

Ishimura, Masakazu, et al. "Effects of KP-496, a Novel Dual Antagonist for Leukotriene D4 and Thromboxane A2 Receptors, On Contractions Induced By Various Agonists in the Guinea Pig Trachea." Allergology International : Official Journal of the Japanese Society of Allergology, vol. 55, no. 4, 2006, pp. 403-10.
Ishimura M, Kataoka S, Suda M, et al. Effects of KP-496, a novel dual antagonist for leukotriene D4 and thromboxane A2 receptors, on contractions induced by various agonists in the guinea pig trachea. Allergol Int. 2006;55(4):403-10.
Ishimura, M., Kataoka, S., Suda, M., Maeda, T., & Hiyama, Y. (2006). Effects of KP-496, a novel dual antagonist for leukotriene D4 and thromboxane A2 receptors, on contractions induced by various agonists in the guinea pig trachea. Allergology International : Official Journal of the Japanese Society of Allergology, 55(4), 403-10.
Ishimura M, et al. Effects of KP-496, a Novel Dual Antagonist for Leukotriene D4 and Thromboxane A2 Receptors, On Contractions Induced By Various Agonists in the Guinea Pig Trachea. Allergol Int. 2006;55(4):403-10. PubMed PMID: 17130683.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effects of KP-496, a novel dual antagonist for leukotriene D4 and thromboxane A2 receptors, on contractions induced by various agonists in the guinea pig trachea. AU - Ishimura,Masakazu, AU - Kataoka,Sayuri, AU - Suda,Masahiro, AU - Maeda,Takashi, AU - Hiyama,Yoshiyuki, PY - 2006/01/30/received PY - 2006/04/26/accepted PY - 2006/11/30/pubmed PY - 2007/4/4/medline PY - 2006/11/30/entrez SP - 403 EP - 10 JF - Allergology international : official journal of the Japanese Society of Allergology JO - Allergol Int VL - 55 IS - 4 N2 - BACKGROUND: A dry powder inhaler of KP-496 is currently in clinical development in Japan as an anti-asthmatic agent. The aim of this study was to evaluate the in vitro pharmacological profile of KP-496. METHODS: The antagonistic activities of KP-496 for leukotriene (LT) D(4) and thromboxane (TX) A(2) receptors were examined using the LTD(4)- and U46619-induced contractions of the isolated guinea pig trachea. The selectivity of KP-496 was examined using various agonist-induced contractions in the isolated guinea pig trachea. RESULTS: KP-496 produced parallel rightward shifts of the LTD(4) and U46619 concentration-response curves in a concentration-dependent manner. Schild plot analyses of the antagonistic activities of KP-496 demonstrated that it is a competitive antagonist for LTD(4) and TXA(2) receptors with pA(2) values of 8.64 and 8.23, respectively. The LTD(4) antagonistic activity of KP-496 was comparable to that of pranlukast and zafirlukast but was more potent than that of montelukast. The TXA(2) antagonistic activity of KP-496 was comparable to that of seratrodast. KP-496 and seratrodast also inhibited the prostaglandin (PG) D(2)- and PGF(2alpha)-induced contractions of the isolated guinea pig trachea. KP-496 had no effect on the histamine-, acetylcholine-, serotonin- and substance P-induced contractions of the isolated guinea pig trachea. CONCLUSIONS: These results indicate that KP-496 is a selective dual antagonist for LTD(4) and TXA(2) receptors. LTD(4) and TXA(2) play important roles in asthma, and antagonists for these mediators are being used for the treatment of asthma. Thus, KP-496 is expected to become a novel potent therapeutic agent for asthma. SN - 1323-8930 UR - https://www.unboundmedicine.com/medline/citation/17130683/Effects_of_KP_496_a_novel_dual_antagonist_for_leukotriene_D4_and_thromboxane_A2_receptors_on_contractions_induced_by_various_agonists_in_the_guinea_pig_trachea_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1323-8930(15)30996-5 DB - PRIME DP - Unbound Medicine ER -